The Role of Membrane Attack Complex in Atypical Haemolytic Uraemic Syndrome

非典型溶血性尿毒症综合征(AHUS)是一种肾脏疾病，如不治疗可迅速进展为肾功能衰竭。直到最近，由于复发率高，肾移植一直是禁忌。在过去的20年里，对aHUS的研究发现，它是由于补体系统失去整合调节而过度激活的结果。补体系统是一种古老的防御机制，它保护身体免受外来细胞的伤害，并清除我们自己受损的细胞。在某些情况下，人们缺乏调节补体系统的能力，这反过来又允许补体系统攻击健康组织，从而导致疾病。在aHUS患者中，关键补体蛋白的基因突变会导致产生缺陷蛋白，从而无法正常发挥功能，这反过来又会导致他们患上疾病。在研究表明补体系统在aHUS中的作用后，它导致了药物Eculizumab的使用，改变了患者的生活。这种药物的工作原理是关闭补体系统的最终途径，防止对健康细胞的直接攻击，并防止炎症环境的产生。然而，这种药物非常昂贵，而且它会使人体对外来细胞的一种防御系统消失，从而使人们容易受到严重的、危及生命的感染。有鉴于此，我们开发了一个aHUS的比较模型，该模型将使我们能够研究补体系统的‘末端通路’。我的实验将确定末端通路中的哪种蛋白质负责疾病的发展。一旦我们确定了蛋白质在疾病中的作用，我们将能够通过使用靶向药物治疗来抑制其功能。这将证实我们对疾病基本机制的理解，同时在临床前模型中测试靶向治疗。这将使我能够为患者开发和提供有针对性的治疗；降低他们感染增加的风险，并改善所有人的卫生经济。我的实验将提供关于目前一线抗补体疗法在这一模型中的疗效的详细数据，并将在未来的临床前评估中提供大量信息并决定新的补体疗法是否能为患者提供更好的保护。从败血症到脊髓损伤，补体系统的末端通路对更多疾病的发展至关重要。了解末端途径蛋白在补体失调模型(我的aHUS比较模型)中的作用将大大有助于提高整体理解；为各种疾病产生可翻译的益处，并开始提供对这些条件下的抗补体治疗的理解。

Atypical haemolytic uraemic syndrome (aHUS) is a kidney disorder which without treatment rapidly progresses to kidney failure. Until recently, renal transplantation has been contraindicated due to the high recurrence rate. Over the last 20 years research into aHUS has found that it results from over activation of the complement system due to loss of its integral regulation. The complement system is an ancient defence mechanism which protects the body from foreign cells and removes our own damaged ones. In certain conditions, people lack the ability to regulate the complement system, this in turn allows the complement system to attack healthy tissue which subsequently causes disease. In aHUS people have genetic mutations for key complement proteins, this results in a defective protein being produced, which is unable to function normally, this in turn then causes them to develop disease. After research had shown the role of the complement system in aHUS, it led to the use of the drug 'Eculizumab' which has transformed patients' lives. This drugs works by 'switching' off the final pathway of the complement system, preventing the direct attack on healthy cells and preventing the creation of an inflammatory environment. However, the drug is very costly and as it silences one of the body's defences against foreign cells it can make people vulnerable to serious, life threatening infections. In light of the above we have developed a comparative model of aHUS which will allow us to investigate the 'terminal pathway' of the complement system. My experiments will determine which protein of the terminal pathway is responsible for the development of disease. Once we have defined the proteins role in disease we will be able to inhibit its function by using a targeted drug therapy. This will confirm our understanding of the basic mechanisms of the disease whilst simultaneously testing a targeted therapy in a pre-clinical model. This will enable me to develop and deliver a targeted treatment for patients; reducing their risks of increased infection and improve health economics for all. My experiments will provide detailed data regarding the efficacy of the current front line anti-complement therapy in this model, and will heavily inform and dictate whether new complement therapeutics in pre-clinical evaluation can provide better protection for patients in the future. The terminal pathway of the complement system is critical to the development of many more diseases; stemming from sepsis to spinal cord injury. Understanding the roles of the terminal pathway proteins in a model of complement dysregulation (my comparative model of aHUS) will significantly contribute to an improved overall understanding; producing translatable benefits to a wide variety of disease and begin to provide an understanding of anti-complement therapies in these conditions.